Implementing genomic medicine in clinical care of deaf patients

在聋哑患者的临床护理中实施基因组医学

• 批准号: 9757749
• 负责人: XUE Z LIU
• 金额: $ 64.5万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-08 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757749
• 关键词: Address; Adult; Animal Model; Area; Attitude; Basic Science; Behavior; Bioinformatics; Biology; CRISPR/Cas technology; Candidate Disease Gene; Caring; Cell Therapy; Cells; Child; Clinic; Clinical; Clinical assessments; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA; Data; Databases; Detection; Diagnosis; Diagnostic; Electrophysiology (science); Etiology; Family; Feasibility Studies; Foundations; Gene Expression Profiling; Genes; Genetic; Genetic Counseling; Genome; Genomic approach; Genomic medicine; Genomics; Genotype; Grant; Hair Cells; Health Status; Hearing; Human; Individual; Infrastructure; International; Knock-in Mouse; Knowledge; Laboratories; Labyrinth; Language Development; Mediating; Medical; Medical Records; Minority; Modeling; Molecular; Mus; Mutation; Nucleic Acids; Outcome; Participant; Patient Care; Patients; Phenotype; Physiology; Population; Procedures; Proteins; Protocols documentation; Quality of Care; Recovery of Function; Role; Sampling; Speech Development; Surveys; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Translating; Universities; Variant; accurate diagnosis; base; causal variant; clinical care; clinical database; clinical practice; cohort; cost effectiveness; database of Genotypes and Phenotypes; deaf; deafness; exome; experimental study; functional genomics; gene discovery; gene therapy; genetic deafness; genetic variant; genome editing; genome sequencing; genomic data; genomic profiles; genomic tools; genomic variation; hearing impairment; hearing restoration; hearing screening; human model; improved; in vivo; induced pluripotent stem cell; innovation; insight; next generation sequence data; normal hearing; novel; novel therapeutics; phenotypic data; pre-clinical; precision medicine; preclinical study; progenitor; repository; research clinical testing; screening; screening program; tool

Abstract: This continuing proposal will translate basic research utilizing high-throughput genomic approaches and functional genomics into routine diagnostic and therapeutic tools for non-syndromic hearing loss (NSHL), the most common type of hearing impairment in children and adults. We have developed a genomic variant detection platform MiamiOtogenomics - composed of MiamiCapitalArray/MiamiOtoGenes panels/exome (WES)/genome (WGS) and developed a genotype and phenotype database – MiamiGeneHeal. As shown in the preliminary data, we have already collected approximately 3,000 DNA samples with phenotypic data from a large international cohort (Miami Otogenetic Repository) of families with NSHL. Moreover, we have excluded all known HL genes in over 200 families, successfully identified more than 18 potential new candidate genes, created animal models for human HL, and have generated human iPSCs from patients with genetic deafness. We will build on these accomplishments and preliminary data by proposing to complete the following specific aims: 1. Apply an innovative genomics-based MiamiOtogenomics pipeline for NSHL; 2. Identify factors influencing the decision to pursue and act on genomic testing; 3. Initiate preclinical therapeutic experiments as a proof-of-concept for potential treatments for HL. The foundation of the proposal will leverage the exceptional genomics capacity of collaborators at the University of Miami into a genomic-based, minority-focused, diagnostic and treatment pipeline for HL. The overarching purpose of this application is to transit discoveries made in laboratory to patient care. This study will translate genomic analysis into clinical hearing screening to elucidate the exact molecular etiology for HL, which will enable more accurate diagnoses, better quality of care, more effective genetic counseling, as well as improved cost-effectiveness in medical care. In addition, we expect to contribute significantly to genotype-phenotype studies and to establish a robust framework for assessing long-term clinical outcomes. Moreover, this study will contribute to our fundamental understanding of HL. Finally, our innovative preclinical therapeutic experiments in our knockin mouse and human iPSC models using CRISPR will potentially discover new treatments for HL. This study will inform two important clinical aspects of precision medicine in USA populations, especially in USA minorities: general acceptance in clinical practice and clinical utility. We will perform one of the largest and most integrated clinical/genomic/functional/novel therapeutic studies on NSHL to date. Our prior results, the interdisciplinary team's expertise and our established study infrastructure and population access support feasibility of our Aims.

摘要：这项持续提案将利用高通量基因组方法转化基础研究，并 将功能基因组学纳入非综合征性听力损失（NSHL）的常规诊断和治疗工具中，这是最常见的 儿童和成人听力障碍的类型。我们开发了基因组变异检测平台 MiamiOtogenomics - 由 MiamiCapitalArray/MiamiOtoGenes panel/外显子组 (WES)/基因组 (WGS) 和 开发了基因型和表型数据库——MiamiGeneHeal。如初步数据所示，我们已经 从大型国际队列中收集了大约 3,000 个带有表型数据的 DNA 样本（迈阿密 Otogene NSHL 家庭的信息库）。此外，我们还成功排除了 200 多个家族中所有已知的 HL 基因 鉴定了超过 18 个潜在的新候选基因，创建了人类 HL 动物模型，并产生了人类 来自遗传性耳聋患者的 iPSC。我们将在这些成就和初步数据的基础上提出 完成以下具体目标： 1. 将基于基因组学的创新型 MiamiOtogenomics 流程应用于 NSHL； 2. 确定影响基因组检测决定并采取行动的因素； 3. 启动临床前治疗实验 作为 HL 潜在治疗方法的概念验证。该提案的基础将利用卓越的基因组学 迈阿密大学合作者进行基于基因组、以少数族裔为重点的诊断和治疗的能力 HL 的管道。该应用程序的首要目的是将实验室的发现转移到患者护理中。这 研究将基因组分析转化为临床听力筛查，以阐明 HL 的确切分子病因学， 这将实现更准确的诊断、更好的护理质量、更有效的遗传咨询以及改进的 医疗保健的成本效益。此外，我们期望对基因型-表型研究和 建立一个强大的框架来评估长期临床结果。此外，这项研究将有助于我们 对 HL 的基本了解。最后，我们在敲入小鼠中进行的创新临床前治疗实验 使用 CRISPR 的人类 iPSC 模型将有可能发现 HL 的新疗法。这项研究将提供两个重要信息 精准医疗在美国人群中的临床方面，尤其是美国少数族裔：临床普遍接受 实践和临床实用性。我们将进行规模最大、综合性最强的临床/基因组/功能/新颖研究之一 迄今为止 NSHL 的治疗研究。我们之前的结果、跨学科团队的专业知识和我们既定的研究 基础设施和人口准入支持我们目标的可行性。